Case Studie

Data-independent acquisition quantitative proteomics

Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia

Journal：Immunity       Impact Factor：32.4 Time：2022       Author Affiliation：The Francis Crick Institute, UK

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Introduction

Sepsis due to secondary co-infection is frequently encountered in severe COVID-19 infection. The underlying causes of pathologies such as coagulopathy and the mechanisms that counter them to reduce mortality during acute systemic infection are poorly understood.This study utilised different mouse models (n=6) for histological studies, immunofluorescence imaging as well as pathological studies to investigate the relationship between actin and DNase. Next, neutrophil assays, DNA degradation assays and proteomic analyses were performed using different populations (HD=50, SP=36, CP=87) to find that T cell-dependent actin release was associated with defective extracellular chromatin clearance and compensatory endonuclease upregulation. The proteomic analysis was also used to investigate the regulation and impact of extracellular chromatin clearance on SARS-CoV-2 pathology.

Fig.1 Graphical abstract

Fig.2 Low DNase activity is associated with increased COVID-19 mortality

Conclusion

Chromatin accumulation increases mortality in patients with severe SARS-CoV-2, so chromatin clearance plays a key role in the survival of patients with severe SARS-CoV-2. In our experiments, G-actin did not inhibit NET dissolution, suggesting potential contributions from DNase I L3 or other plasma factors. However, actin correlated with reduced DNA and NET degradation capacity in SARS-CoV-2-infected individuals and triggered compensatory mechanisms in sepsis that underline the stress that actin exerts on these pathways. T cell apoptosis plays a critical pathogenic role through systemic chromatin accumulation. Targeting extracellular chromatin may prove more beneficial than anti-cytokine monotherapies because chromatin induces multiple inflammatory cytokines and immune dysfunction. The link between chronic inflammation and low NETase activity may explain the association of CP susceptibility with inflammatory conditions. The similar trends with plasma proteome correlations between SARS-CoV-2-infected and HDinfl individuals suggested that low NETase activity had a similar impact on physiology in both groups. As NET degradation measurements were robust enough to sub-stratify samples, plasma proteomics enabled the characterization of samples that were otherwise difficult to distinguish by conventional clinical approaches, identifying high-risk individuals within clinically indistinguishable cohorts and pre-clinical states that may predispose individuals to acute or chronic disease.

Reference

Aramburu I V, Hoving D, Vernardis S I, et al. Functional proteomic profiling links deficient DNA clearance with increased mortality in individuals with severe COVID-19 pneumonia[J]. Immunity, 2022